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Gene Therapy for Fanconi Anemia

August 2012

Pamela S. Becker, MD PhD

Pamela S. Becker, MD PhD

Fanconi anemia is an inherited disorder where patients have a defect in their ability to repair damaged DNA. It leads to progressively lower levels of blood cells and higher chances for developing acute leukemia or other cancers. The treatments available today include medications or transfusions to increase the patient's blood counts. The only potential cure for the low blood counts in Fanconi anemia is a bone marrow transplant from a person who does not carry the disorder. However, not all patients have a suitably matched donor for a bone marrow transplant, and the transplant is a very risky procedure for Fanconi anemia patients.

We have been developing a gene therapy clinical trial for patients with Fanconi complementation group A, the most common type of Fanconi anemia. Our study attempts to correct the patient's bone marrow stem cells by using a modified virus that can transfer the normal gene to the patient without causing an infection. The viruses used for this purpose previously were called gammaretroviruses, but we will use a new type of virus for Fanconi anemia gene therapy, called a lentivirus. The purpose of this study is to correct the defect in the patient's own bone marrow and blood cells.

The vector carrying the normal Fanconi A gene was constructed in Dr. Kiem's lab here at the Fred Hutchinson Cancer Research Center. A vector is a biological tool for delivering gene therapy. It consists of a virus carrying a normal gene that is designed to replace the patient's defective gene. Standard molecular biology methods are used to clone the normal gene and insert it into the viral backbone. All the modifications for gene expression, safety modifications, and other elements were performed here.

The patient begins the process by taking a growth factor called G-CSF which mobilizes blood-forming stem cells from the bone marrow into the blood. After receiving G-CSF injections for a few days, the patient has special IVs placed that connect via tubing to a machine for a procedure called leukapheresis. The patient's blood circulates into the machine, a portion of the white blood cells including the blood-forming stem cells is retained in a collection bag, and most of the other blood elements such as the red blood cells and platelets are returned to the patient. For patients age 18 and older, we will also use a second drug called plerixafor, which helps increase the yield of stem cells in the peripheral blood. For patients for whom we don't collect enough cells in this way, we may also aspirate bone marrow.

Once enough of the patient's stem cells have been harvested, they are treated in the laboratory to add the normal gene. First, the stem cells are selected from any other blood cells present by using magnetic bead separation techniques. Then the cells are incubated in low oxygen at body temperature, in combination with special factors and the lentivirus. The lentivirus combines with the patient's DNA and the normal gene for Fanconi type A remains in the DNA of the patient's cells, while the rest of the virus is degraded.

As soon as possible after the normal gene is inserted, the cells can be infused back into the patient like a regular blood transfusion. We will then see if the patient's blood counts improve after this treatment, and monitor the patient's blood and bone marrow for the presence of the gene corrected cells over a period of months to years.

This clinical trial is now open for adult patients, and we hope to open it in the future to children as well. Gene therapy has been used in clinical trials for other inherited conditions that affect the ability of blood-forming stem cells to develop into a normal blood and immune system. These include severe combined immunodeficiency disease (SCID), Wiskott-Aldrich syndrome (WAS), and chronic granulomatous disease (CGD), as well as others. For more information about this trial, please contact the research coordinator Jennifer Adair, PhD, at jadair@fhcrc.org

Pamela S. Becker, MD, PhD is an Associate Professor at the University of Washington School of Medicine. Growing up as the child of a pathologist, she knew at an early age that she wanted to be a doctor. Dr. Becker has both an MD and a PhD from Harvard, and did her Hematology fellowship at Yale. She has long been fascinated by inherited blood disorders, and divides her time between clinical patient care and research on the behavior of blood cells. Dr. Becker is also married to a physician and has two daughters who are interested in biomedical research. Her other passions are playing the violin and volunteering for patient support groups.